Genome-Wide Association Studies of Schizophrenia and Bipolar Disorder in a Diverse Cohort of US Veterans

Background: Schizophrenia (SCZ) and bipolar disorder (BIP) are debilitating neuropsychiatric disorders, collectively affecting 2% of the world\u27s population. Recognizing the major impact of these psychiatric disorders on the psychosocial function of more than 200 000 US Veterans, the Department of Veterans Affairs (VA) recently completed genotyping of more than 8000 veterans with SCZ and BIP in the Cooperative Studies Program (CSP) #572. Methods: We performed genome-wide association studies (GWAS) in CSP #572 and benchmarked the predictive value of polygenic risk scores (PRS) constructed from published findings. We combined our results with available summary statistics from several recent GWAS, realizing the largest and most diverse studies of these disorders to date. Results: Our primary GWAS uncovered new associations between CHD7 variants and SCZ, and novel BIP associations with variants in Sortilin Related VPS10 Domain Containing Receptor 3 (SORCS3) and downstream of PCDH11X. Combining our results with published summary statistics for SCZ yielded 39 novel susceptibility loci including CRHR1, and we identified 10 additional findings for BIP (28 326 cases and 90 570 controls). PRS trained on published GWAS were significantly associated with case-control status among European American (P \u3c 10-30) and African American (P \u3c .0005) participants in CSP #572. Conclusions: We have demonstrated that published findings for SCZ and BIP are robustly generalizable to a diverse cohort of US veterans. Leveraging available summary statistics from GWAS of global populations, we report 52 new susceptibility loci and improved fine-mapping resolution for dozens of previously reported associations

Software Metrics: An Analysis and Evaluation

Software metrics is a new area of computer science designed to enable programmers and other practitioners to assign quantitative indexes of merit to software. In this volume, "software" is defined broadly as a generic for all the stages of tailoring a computer system to solve a problem. Software Metrics is the first book to survey this new area, measuring its present extent, describing its characteristic features, and indicating directions of potential expansion.The aim of the articles included in the book is to provide precise, quantified answers to such questions as: What are the memory requirements of the software? The speed requirements? What is the cost of production? The likely time schedule of production? When will it have to be replaced? What manpower loading should be used? how close to its limits is the system expected to run? What levels of satisfactory testing are sufficient? How well does the testing environment approximate the execution environment? What is the enhancement cost? To what extent has the problem—of the technology—moved beyond the program? Would it cost less to rebuild the system than to maintain and enhance it?"In software, evolutionary complexity is probably more important than the classical time and space measures with which computer science has been concerned so far," the editors note in their introductory overview. This overview gauges the range of the book's fifteen contributions by the major developers of software metrics.</p

Exploring Issues of Quality of Service in a Next Generation Internet Testbed: A Case Study Using PathMaster

This case study describes a project that explores issues of quality of service (QoS) relevant to the next-generation Internet (NGI), using the PathMaster application in a testbed environment. PathMaster is a prototype computer system that analyzes digitized cell images from cytology specimens and compares those images against an image database, returning a ranked set of “similar” cell images from the database. To perform NGI testbed evaluations, we used a cluster of nine parallel computation workstations configured as three subclusters using Cisco routers. This architecture provides a local “simulated Internet” in which we explored the following QoS strategies: (1) first-in-first-out queuing, (2) priority queuing, (3) weighted fair queuing, (4) weighted random early detection, and (5) traffic shaping. The study describes the results of using these strategies with a distributed version of the PathMaster system in the presence of different amounts of competing network traffic and discusses certain of the issues that arise. The goal of the study is to help introduce NGI QoS issues to the Medical Informatics community and to use the PathMaster NGI testbed to illustrate concretely certain of the QoS issues that arise

Gene-Based and Pathway-Based Genome-Wide Association Study of Alcohol Dependence

Background: The organization of risk genes within signaling pathways may provide clues about the converging neurobiological effects of risk genes for alcohol dependence. Aims: Identify risk genes and risk gene pathways for alcohol dependence. Methods: We conducted a pathway-based genome-wide association study (GWAS) of alcohol dependence using a gene-set-rich analytic approach. Approximately one million genetic markers were tested in the discovery sample which included 1409 European-American (EA) alcohol dependent individuals and 1518 EA healthy comparison subjects. An additional 681 African-American (AA) cases and 508 AA healthy subjects served as the replication sample. Results: We identified several genome-wide replicable risk genes and risk pathways that were significantly associated with alcohol dependence. After applying the Bonferroni correction for multiple testing, the \u27cellextracellular matrix interactions\u27 pathway (p\u3c2.0E-4 in EAs) and the PXN gene (which encodes paxillin) (p=3.9E-7 in EAs) within this pathway were the most promising risk factors for alcohol dependence. There were also two nominally replicable pathways enriched in alcohol dependence-related genes in both EAs (0.015≤p≤0.035) and AAs (0.025≤p≤0.050): the \u27Na+/Cl- dependent neurotransmitter transporters\u27 pathway and the \u27other glycan degradation\u27 pathway. Conclusions: These findings provide new evidence highlighting several genes and biological signaling processes that may be related to the risk for alcohol dependence

Cooperative studies Program (CSP) #572: A study of serious mental illness in veterans as a pathway to personalized medicine in schizophrenia and bipolar illness

Personalization of psychiatric treatment includes treatment of symptoms, cognition and functional deficits, suicide, and medical co-morbidities. VA Collaborative Study 572 examined a large sample of male and female veterans with schizophrenia (n = 3,942) and with bipolar disorder (n = 5,414) with phenotyping and genomic analyses. We present the results to date and future directions. All veterans received a structured diagnostic interview and assessments of suicidal ideation and behavior, PTSD, and health. Veterans with schizophrenia were assessed for negative symptoms and lifetime depression. All were assessed with a cognitive and functional capacity assessment. Data for genome wide association studies were collected. Controls came from the VA Million Veteran Program. Suicidal ideation or behavior was present in 66%. Cognitive and functional deficits were consistent with previous studies. 40% of the veterans with schizophrenia had a lifetime major depressive episode and PTSD was present in over 30%. Polygenic risk score (PRS) analyses indicated that cognitive and functional deficits overlapped with PRS for cognition, education, and intelligence in the general population and PRS for suicidal ideation and behavior correlated with previous PRS for depression and suicidal ideation and behavior, as did the PRS for PTSD. Results to date provide directions for personalization of treatment in SMI, veterans with SMI, and veterans in general. The results of the genomic analyses suggest that cognitive deficits in SMI may be associated with general population features. Upcoming genomic analyses will reexamine the issues above, as well as genomic factors associated with smoking, substance abuse, negative symptoms, and treatment response